Neo Blood Vessels- Phase 1 Flashcards
ReKap
May-Thurner syndrome (MTS) is a rare anatomic variant usually seen in young women, characterized by outflow obstruction of the left common iliac vein.
Obstruction is due to compression by the overlying right common iliac artery and can be precipitated by posterior compression against the lumbar vertebral column by a gravid uterus.
Venous outflow obstruction, along with hypercoagulability associated with pregnancy, both increase the risk of deep venous thrombosis.
Analysis
The correct answer E. The patient’s symptoms are consistent with deep venous thrombosis that may be precipitated by May-Thurner syndrome (MTS), which is a rare condition that is associated with venous outflow obstruction.
MTS is caused by compression of the left common iliac vein by the right common iliac artery and can be precipitated by a gravid uterus. In ~22% of individuals, the left common iliac vein is trapped between an overlying right common iliac artery and the lumbar vertebral column posteriorly (see figure). Compression causes the vein to collapse, which obstructs venous outflow from the lower extremities. Outflow obstruction leads to venous stasis, which increases the risk of thrombosis. The likelihood of thrombosis is increased by a rise in procoagulant and clotting factor production during pregnancy and is a major contributor to thrombosis in MTS. This patient has a deep venous thrombosis (DVT), which most likely developed as a complication of her pregnancy.
Risk factors associated with MTS are similar to the risk factors for venous thromboembolism (VTE) in nonpregnant patients, although pregnancy itself carries a five-fold increased risk for VTE. Prior VTE is the most important risk factor. Other risk factors include obesity, multiple pregnancies, scoliosis, and prior radiation exposure. MTS can occur antepartum but is most common in the postpartum period (usually within the first 6 weeks after delivery). Delivery by cesarean section is also associated with a 3-fold increased risk for postpartum VTE.
The diagnosis of DVT can be confirmed by duplex compression ultrasonography of the affected extremity. Anticoagulation with low-molecular-weight heparin (enoxaparin) is the treatment of choice for patients with DVT related to MTS, and is also used for prophylaxis in select high-risk pregnant patients.
Arterial embolism (choice A) to the lower extremity is a surgical emergency associated with acute onset of the six Ps: pain, pallor, poikilothermia (temperature variation), pulselessness, paresthesia (tingling and numbness), and paralysis. Arterial embolism does not present with chronic leg swelling and pain after pregnancy. Emboli most commonly originate from the heart in patients with arrhythmias or heart failure, neither of which are included in this patient’s medical history.
Claudication (choice B) is associated with peripheral artery disease. It is unlikely that this young, otherwise healthy woman without evidence of atherosclerotic disease has peripheral artery disease. Claudication usually presents with bilateral (instead of unilateral) leg pain. Peripheral artery disease and claudication are not common complications that develop after pregnancy.
Congestive heart failure (choice C) is also unlikely in a young physically active woman without a prior history of heart disease. Congestive heart failure due to peripartum cardiomyopathy can sometimes develop after pregnancy and can persist in some cases, leading to chronic disease. Heart failure typically presents with bilateral lower extremity edema rather than unilateral swelling.
Lymphedema (choice D) is caused by injury to lymphatic vessels and obstruction of lymphatic flow. The increase in pressure within the lymphatic system will then lead to extravasation of fluid into the interstitial space, causing edema. Lymphedema is associated with malignancy (tumor cells block lymphatic flow), radiation exposure, prior surgeries (lymph node resection in malignancy), and certain parasitic infections, such as filariasis. Although it can cause unilateral leg swelling and pain, it is not a common chronic complication of pregnancy.
ReKap
Terazosin is an alpha-1 adrenergic receptor antagonist indicated for the treatment of hypertension and benign prostatic hyperplasia (BPH).
Terazosin decreases arteriole and venous resistance and decreases the tone of urinary sphincters.
Side effects include syncope/hypotension and dizziness that are postural in nature.
Analysis
The correct answer is B. Terazosin is an alpha-1 adrenergic receptor antagonist (as are prazosin and doxazosin) indicated for the treatment of hypertension and benign prostatic hyperplasia (BPH). For the treatment of hypertension, terazosin decreases arteriolar and venous resistance by antagonizing alpha-1 receptors on these vessels. For the treatment of BPH, they decrease urinary frequency and nocturia by decreasing the tone of urinary sphincters. Notable side effects include syncope/hypotension and dizziness. It is important to note that orthostatic hypotension can be seen with most (if not all) antihypertensive agents; however, hyperacute “first-dose” syncope and orthostatic hypotension is most commonly associated with the alpha-1 receptor antagonists and periodically with angiotensin-converting enzyme (ACE) inhibitors.
Finasteride and dutasteride are 5-alpha-reductase inhibitors (choice A) that act by blocking the conversion of testosterone to 5-alpha-dihydrotestosterone. They are used in the treatment of symptomatic prostatic hyperplasia; however, they are not associated with orthostasis of hypotension.
Enalapril is an example of an ACE inhibitor (choice C). ACE inhibitors are indicated for the treatment of hypertension and congestive heart failure. When ACE is inhibited, it prevents the conversion of angiotensin I to angiotensin II, leading to a decrease in aldosterone levels. Important side effects include hyperkalemia, angioedema, hypotension, and cough. While ACE inhibitors can be associated with orthostasis and hypotension, they have no role in the treatment of BPH.
Atenolol is an example of a beta-1 receptor antagonist (choice D) used for the treatment of hypertension, angina, and post-myocardial infarction cardiovascular event prevention. Side effects include bradycardia, heart block, heart failure, orthostatic hypotension, and bronchospasm (at higher doses). Beta-1 receptor antagonists have no role in the treatment of BPH.
The calcium channel blockers (CCBs) act by blocking the L-type calcium channels in the heart (choice E) and blood vessels (choice F). Verapamil and diltiazem are used as antiarrhythmics, and all CCBs are used for hypertension and angina. “-Dipines” include drugs such as amlodipine and felodipine. These agents would not be used for BPH. These drugs can cause cardiac depression, peripheral edema, dizziness, orthostatic hypotension, reflex tachycardia (“-dipines”), gingival hyperplasia (“-dipines”), and constipation (verapamil).
ReKap
External iliac artery hemorrhage is a dangerous and potentially life-threatening complication of percutaneous arterial access.
The femoral artery is the preferred location for arterial access because it allows for easier control of bleeding after vascular sheath removal.
Analysis
The correct answer is C. When catheterizing the femoral artery for a procedure such as cardiac catheterization or angioembolization, it is important to confirm the location of the arterial puncture site. If the patient is punctured too high above the inguinal ligament, there will be nothing to compress the arteriotomy site when the sheath is removed. The external iliac artery becomes the femoral artery when it passes inferior to the inguinal ligament. A properly placed arterial puncture allows the femoral artery to be compressed against the femoral head to obtain hemostasis. If the external iliac artery is hemorrhaging, vascular surgery should be consulted for cutdown and repair of the bleeding artery.
Anatomical distribution of arteries supplying the lower limbs. Catheterization above the inguinal ligament can result in catheterization of the external iliac artery, which can lead to lethal hemorrhaging.
Abdominal aorta (choice A) is too deep within the abdomen to have been punctured during groin arterial catheterization.
The common iliac artery (choice B), which branches from the abdominal aorta, would be too proximal and deep within the abdomen to be punctured.
The femoral artery (choice D) is the artery that should be catheterized because it allows for compression against the femoral head after sheath removal. It is not named the femoral artery until it is inferior to the inguinal ligament.
The internal iliac artery (choice E) branches off the common iliac artery and proceeds deep within the pelvis.
The profunda femoris artery (choice F) branches from the femoral artery and would be too distal for a puncture site. The catheterization of the profunda femoris artery is associated with pseudoaneurysms.
ReKap
Amphetamines increase blood pressure primarily by inducing nerve terminals to release stored norepinephrine (NE) into the synapse.
Increases in synaptic NE cause peripheral vasoconstriction via alpha-1 receptor stimulation and tachycardia via beta-1 receptor stimulation.
Analysis
The correct answer is G. Methamphetamine, an indirect-acting sympathomimetic, is a stimulant that causes hypertension and tachycardia by inducing norepinephrine (NE) release. Methamphetamine causes the release of the mobile (non-vesicular) pool of norepinephrine, causing an increase in the synaptic concentration of NE and thus greater stimulation of postsynaptic receptors. The receptors that mediate:
systemic vasoconstriction are alpha-1 adrenergic receptors
increases in heart rate and inotropic state are beta-1 adrenergic receptors
Amphetamines are called indirect-acting sympathomimetics because they indirectly stimulate postsynaptic receptors via neurotransmitter release. Increases in central NE also occur. Symptoms of methamphetamine toxicity include central nervous system stimulation, anxiety, emotional lability, psychosis, tachycardia, hypertension, diaphoresis, and mydriasis.
- Methyl-para-tyrosine (blocks the rate-limiting enzyme of catecholamine synthesis).
- Monoamine oxidase (MAO) inhibitors (phenelzine, tranylcypromine).
- Releasers (amphetamines, methylphenidate).
- Reuptake blockers (cocaine).
- Alpha-2 agonists (clonidine) and antagonists (mirtazapine).
- Reserpine (depletes neurotransmitters by preventing uptake into vesicles and damaging vesicles).
- Guanethidine (inhibits NE release).
- Agonists and antagonists of alpha-1 and beta-2 receptors.
Blockade of dopamine reuptake (choice A) is responsible for the reinforcing and other central effects of cocaine. Methamphetamine may impair reuptake also, but dopamine is responsible for the reinforcing effects and does not affect blood pressure.
Direct stimulation of alpha-1 receptors (choice B) would increase blood pressure, but this is not methamphetamine’s mechanism of action.
Direct stimulation of beta-1 receptors (choice C) could increase blood pressure by increasing the inotropic state, but this is not methamphetamine’s mechanism of action.
Direct stimulation of beta-2 receptors (choice D) would cause vasodilation in the skeletal muscle vasculature, leading to a decrease in blood pressure. Methamphetamine does not directly stimulate beta-2 receptors.
Increasing dopamine release (choice F) in the central nervous system is likely responsible for the reinforcing effects and other central properties of the methamphetamine. Increases in synaptic dopamine would cause increased stimulation of postsynaptic dopamine-2 receptors (choice E). Methamphetamine does not directly stimulate dopamine receptors.
ReKap
The carotid and arterial baroreceptors provide a reflex feedback mechanism designed to stabilize changes in blood pressure and heart rate.
A decrease in systemic arterial pressure leads to a compensatory increase in blood pressure and cardiac output (secondary to an increase in sympathetic outflow and decrease in parasympathetic outflow).
Norepinephrine causes inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) to form in arteriolar smooth muscle cells via α1 receptor stimulation, leading to vasoconstriction; angiotensin II and vasopressin also contribute to this response.
An increase in systemic arterial pressure leads to a compensatory dilation of the arterioles and decreases cardiac output (secondary to a decrease in sympathetic outflow and increase in parasympathetic outflow).
Analysis
The correct answer is G. Low blood pressure is sensed by baroreceptors within the wall of the aortic arch and carotid sinus, triggering a compensatory baroreflex. A baroreflex includes increased sympathetic outflow to small arteries and arterioles (resistance vessels) to increase systemic vascular resistance.
Postganglionic sympathetic nerves innervating small arteries and arterioles release norepinephrine at their terminals. The transmitter then binds to α1-adrenergic receptors on the vascular myocytes.
α1 receptors are G protein-coupled receptors that associate with Gq. Receptor occupancy releases the Gαq-subunit, which triggers phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis (via phospholipase C), forming two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
DAG travels in the membrane to activate protein kinase C.
IP3 is water-soluble and initiates Ca2+ release from intracellular stores, causing intracellular Ca2+ levels to rise.
Ca2+ then binds calmodulin to form a complex that activates myosin light chain kinase (MLCK). The activated form of MLCK phosphorylates myosin light chains, facilitating interactions between myosin and actin and thereby causing smooth muscle contraction.
A decrease in IP3 (choice C) would decrease smooth muscle contraction, further lowering blood pressure. This could be caused by blocking α1 receptors.
Changing intracellular levels of Na+ (choices D and H) is not the mechanism by which α1 receptors affect a cellular response. An example of a receptor that increases intracellular levels of Na+ is the nicotinic cholinergic receptor, a ligand-gated ion channel.
An increase in cAMP (choice E) would lead to smooth muscle relaxation; this is why epinephrine causes vasodilation via the β2 receptor. The increase in cAMP leads to phosphorylation of MLCK, inactivating it and preventing myosin–actin interaction. A decrease in cAMP (choice A) might aid in smooth muscle contraction by allowing more MLCK to be activated. However, this is not the mechanism by which the α1 receptor acts.
An increase in cGMP (choice F) would cause relaxation and vasodilation by dephosphorylating (deactivating) myosin light chain. A decrease in cGMP (choice B) could reverse the relaxation, but this is not the mechanism by which the α1 receptor acts, nor is cGMP the dominant controller of vascular smooth muscle under basal conditions.
ReKap
Unstable angina:
One type of acute coronary syndrome (ACS).
Often caused by rupture of a pre-existing atherosclerotic plaque with superimposed thrombosis in a coronary artery.
Presents clinically as intractable chest pain at rest or progressively worsening chest pain.
Is not relived by rest and nitroglycerin.
No elevation in myocardial enzymes (vs. NSTEMI and STEMI).
Analysis
The correct answer is C. This patient presents with acute coronary syndrome (ACS), which is characterized by intractable angina at rest or worsening episodes of angina. It can be classified into three types:
Unstable angina (UA) – typical ACS symptoms without an elevation in myocardial enzymes (troponin, CK-MB, etc.). The ECG may show variable changes, including ST-segment depression or transient elevation.
Non-ST elevation myocardial infarction (NSTEMI) – typical ACS symptoms with elevation in myocardial enzymes. The ECG may show variable changes, including ST-segment depression or transient elevation and T-wave inversion.
ST-elevation myocardial infarction (STEMI) – typical ACS symptoms with elevated myocardial enzymes. The ECG shows characteristic changes that evolve over a period of weeks, including profound ST-segment elevation and rounding.
ACS commonly results from disruption of a pre-existing atherosclerotic plaque, particularly one with a thin fibrous cap. The inside of these plaques contains tissue factor and cholesterol esters which, when released, result in thrombus formation and occlusion of coronary blood flow. The thrombosis may or may not occur over an area of the vessel involved by an atherosclerotic plaque. Due to a severe and sudden reduction in coronary flow, coronary vasodilators like nitroglycerin may not relieve the angina symptoms. Our patient has unstable angina, which is most likely caused by thrombosis in a branch of the coronary artery.
Coronary artery embolism (choice A) is uncommon. It would present with signs and symptoms of an acute MI, with elevated troponins/CK-MB and associated ST-segment and T-wave changes on ECG. Potential causes include mural thrombus emboli (from an akinetic ventricular wall) or septic emboli from endocarditis.
Coronary artery spasm (choice B) is also thought to cause angina at rest (Prinzmetal angina). While this type of angina is typically severe, it does not have a crescendo pattern. It often occurs patients ages 40 to 60 or as a result of cocaine abuse. Although coronary artery spasm is more likely to occur in the presence of atherosclerotic lesions, the absence of traditional risk factors for atherosclerotic CAD would make angina due to vasospasm more likely. These types of spasms are typically responsive to vasodilators including nitroglycerin and calcium channel blockers.
Coronary artery vasculitis (choice D) is a feared complication of Kawasaki disease. Kawasaki disease presents in small children (age < 5 years) with a several-day history of fever, rash, strawberry tongue, and bilateral conjunctivitis. Treatment includes aspirin (one of the few times when aspirin is indicated in children) and intravenous immunoglobulin (IVIG).
Stable coronary plaques (choice E) usually cause stable angina, which is characterized by chest pain occurring with exertion and relieved with rest. In stable angina, a plaque results in narrowing of the coronary vasculature, but not enough to prevent sufficient blood flow for myocardial demand at rest. During exercise or exertion, which requires additional coronary flow, the narrowing can lead to angina and other symptoms associated with myocardial ischemia. In contrast, the thrombus produced in ACS is completely occlusive, resulting in ischemia symptoms at rest
ReKap
Dengue virus is a single-stranded RNA flavivirus found in tropical or subtropical regions and is transmitted to humans by Aedes aegypti (primarily) or Aedes albopictus mosquitoes.
Clinical findings include nausea/vomiting, rash, headache, retro-orbital/eye pain, muscle aches, joint pain, leukopenia, and a positive tourniquet test.
Plasma leakage, or vascular leak syndrome, can complicate the course of infection with the dengue virus and result in fluid accumulation, shock, and organ damage.
Analysis
The correct answer is D. Plasma leakage, or vascular leak syndrome, can occur due to increased capillary permeability in severe dengue.
DENV is an enveloped, single-stranded, positive-sense RNA flavivirus with 4 serotypes (DENV 1–4) that is transmitted to humans by Aedes aegypti or Aedes albopictus mosquitoes (hence the name “arbovirus”: arthropod-borne). Over a third of the world’s population who live in tropical and subtropical regions are at risk of DENV infection. Infection with DENV may be asymptomatic or present with a broad range of clinical manifestations (see table). The previous classification of DENV infection included a spectrum of 3 diseases (dengue fever, dengue hemorrhagic fever, or dengue shock syndrome) based on the presence of vascular leakage and its clinical consequences (e.g., fluid accumulation, shock). In 2009, the World Health Organization introduced a revised classification of infection with DENV as described below.
The diagnosis of DENV infection is usually established clinically. The laboratory diagnosis of DENV infection includes direct detection of the viral components in the serum by reverse-transcriptase polymerase chain reaction (high specificity; costly), or indirect detection of antibodies against the viral antigens such as nonstructural protein 1 via serologic assays and tests, e.g., enzyme-linked immunosorbent assay (lower specificity; less costly). Treatment of DENV infection is supportive, which mostly consists of maintaining adequate intravascular volume.
Cardiac complications such as acute myocarditis (choice A) are rare with DENV infection. Viral myocarditis is commonly caused by adenovirus, coxsackie B virus, parvovirus B19, HIV, and human herpesvirus-6.
The most common cause of aseptic meningitis (choice B) is infection with enteroviruses (poliovirus, echovirus, and coxsackievirus), which belong to the Picornaviridae. This patient has DENV infection, which would not directly affect the brain tissue or meninges.
Flaccid paralysis (choice C) and parkinsonian features may occur as a result of infection with the West Nile virus. This patient is infected with DENV and is less likely to have flaccid paralysis.
The incidence of encephalitis (choice E) and encephalopathy due to DENV infection is rare. The virus does not directly infect brain cells. Plasma leakage and the associated clinical consequences are more common during DENV infection. Severe infection can cause plasma leakage, leading to an altered mental state and impaired consciousness.
ReKap
Resistances in parallel:
The reciprocal of the total resistance is the sum of the reciprocals of the individual resistances. This formula is 1/RT = 1/R1 + 1/Rn and continues for as many resistances are present in the circuit.
The total resistance is always less than any of the individual resistances.
Adding a parallel resistance (e.g., an arteriovenous anastomosis) lowers the total resistance and decreases arterial blood pressure.
Analysis
The correct answer is C. The figure shows that the five organs are arranged in a parallel vascular circuit. The total resistance (RT) of a parallel circuit is calculated from the sum of the reciprocals of the individual components:
1/RT = 1/R1 + 1/R2 + 1/R3 + 1/R4 + 1/R5
Each organ has a resistance of 0.25 mm Hg·mL·min-1, so:
1/RT = 1/0.25 + 1/0.25 + 1/0.25 + 1/0.25 + 1/0.25
1/RT = 4 + 4 + 4 + 4 + 4 = 20
RT = 1/20 = 0.05 mm Hg·mL·min-1
Note from the equation that removing a parallel resistance (e.g., R1, R2, or R3) increases the total resistance, whereas adding a parallel resistance decreases the total. Although this may seem counterintuitive, it makes sense if one remembers that adding an organ or vessel in the vascular circuit provides an additional way for blood to flow out of the arterial system.
Clinically, an arteriovenous anastomosis adds another parallel resistor, so systemic vascular resistance (SVR = RT) and mean arterial pressure (MAP) drop. Decreasing the number of resistors (occlusion of blood supply to an organ) increases SVR and MAP.
0.01 mm Hg·mL·min-1 (Choice A) correctly identifies that the total resistance should be lower than any of the individual resistances. However, the denominator used in the resistance equation is too low. If the individual resistances were 0.05 mm Hg·mL·min-1 this answer would be correct.
0.02 mm Hg·mL·min-1 (choice B) also correctly identifies that the total resistance of this circuit will be lower than any of the individual resistances. This answer choice is, however, incorrect for the same reason as choice A as it uses a value of 0.10 mm Hg·mL·min-1 for the individual resistances, which is too low.
1.25 mm Hg·mL·min-1 (choice D) uses the equation for resistances in series, not parallel (RT = R1 + Rn). The total resistance of a circuit with resistances in series is simply the sum of all resistances in that circuit.
20.0 mm Hg·mL·min-1 (choice E) would not be seen with any combination of five 0.25 mm Hg·mL·min-1 resistances. This answer is a common error that occurs if the sum of the inverse resistances from the parallel resistance equation is not also inverted. This answer also cannot be correct as the sum of equal resistances in a parallel circuit is always lower than any one resistance in the circuit.
ReKap
Aortic dissection refers to a longitudinal tear in the aortic wall which leads to damage to both the aorta itself and the vessels that branch off of it.
The majority of cases are associated with systemic hypertension, although other associations include Marfan syndrome and Ehlers-Danlos syndrome.
Patients present with acute tearing chest pain that often radiates to the back and/or abdomen.
Analysis
The correct answer is C. This patient has an aortic dissection, which is strongly linked to uncontrolled hypertension (80% of cases). Increased pressure causes intimal tearing. Blood enters the tunica media of the vessel wall and creates a false lumen, which then spreads in an anterograde or retrograde manner.
Key features:
Sharp, tearing chest pain that radiates to the back and moves downward as the dissection progresses.
Common in the ascending aorta, and characteristically develops between the middle and outer thirds of the tunica media.
Ascending aortic dissections are referred to as type A dissections, whereas descending aortic dissections are referred to as type B dissections.
Widened mediastinum can be identified on chest x-ray.
Involvement of the aortic branches causes weakened distal pulses and differential blood pressures in the arms, depending on the location of the dissection.
Most cases reveal hypertension. Hypotension may be seen in cases associated with pericardial tamponade. Fluctuations in overall blood pressure are likely due to aortic arch baroreceptor dysfunction during dissection.
Management requires a reduction in blood pressure and heart rate: typically with a peripheral vasodilator and a beta-blocker. The beta-blocker is essential to prevent vasodilator-induced reflex tachycardia, which may worsen the dissection. Type A dissections typically require surgical intervention following initial medical management.
Common predisposing factors include a history of smoking, a history of coronary artery disease and, prominently, Marfan syndrome (fibrillin) or Ehlers-Danlos syndrome (type III collagen).
Atherosclerosis (choice A) and diabetes mellitus (choice B) are more likely to predispose for myocardial infarction or abdominal aortic aneurysm than for aortic dissection. Abdominal aortic aneurysms are typically asymptomatic but, when ruptured, produce abdominal pain and hypotension, not found in our patient.
Polyarteritis nodosa (choice D) is a vasculitis that affects small-to-medium size vessels, not the aorta. Symptoms are broad and nonspecific, including palpable purpura in skin, renal disease, neurologic manifestations, and gastrointestinal symptoms.
Syphilis (choice E) is more likely to cause thoracic aortic aneurysms than aortic dissection. This is due to involvement and thrombosis of the vasa vasorum supplying the thoracic aortic wall, thus predisposing to aneurysm formation.
ReKap
The infantile form of aortic coarctation is pre-ductal and associated with a patent ductus arteriosus (PDA).
The abnormally low pressure in the aorta distal to the coarctation in combination with the PDA leads to right-to-left shunting through the PDA.
Cyanotic mixed-venous blood flows to the lower extremities through the PDA, mixing with a small amount of oxygenated blood passing through the coarctation.
Analysis
The correct answer is A. Coarctation of the aorta is a narrowing of the aorta distal to the origin of the left subclavian artery. Two types are usually identified based on whether the constriction is found proximal or distal to the opening of the ductus arteriosus (DA): infantile preductal, (A in the figure below) and adult postductal, (B in the figure below).
This infant manifests the characteristic signs of the infantile form of aortic coarctation, which is associated with patent ductus arteriosus (PDA). The stenotic segment is localized proximal to a PDA. Since blood pressure drops distal to the PDA, blood will shunt from the pulmonary artery to the aorta through the PDA. Thus, cyanosis develops in the lower part of the body only.
Postductal coarctation is more common and occurs distal to the DA. In this form, the DA usually closes and obliterates. This results in the intercostal arteries providing collateral circulation between the internal thoracic artery and the thoracic aorta to provide blood supply to the lower parts of the body (see C in the figure). These patients will be hypertensive in the upper body and hypotensive with weak pulses in the lower limbs. Enlargement of the intercostal arteries results in costal notching on the lower border of the ribs.
Anatomical depiction of coarctation of the aorta. Infantile coarctation occurs proximal to ductus arteriosus.”
An isolated PDA (choice B), if large enough, will allow significant left-to-right shunting, resulting in pulmonary overload, secondary pulmonary hypertension, and right ventricular hypertrophy (chronic cor pulmonale). Persistence of PDA is promoted by prostaglandin E2, whereas inhibitors of prostaglandin synthesis (indomethacin or other nonsteroidal anti-inflammatory drugs [NSAIDs]) facilitate closure of the ductus.
Pulmonic stenosis (choice C) is an infrequent form of congenital heart disease that presents with chronic cor pulmonale because of increased resistance to blood flow in the pulmonary artery. Right-sided heart failure develops without cyanosis.
Tetralogy of Fallot (choice D) is one of the most frequent types of congenital heart disease in general and is the most frequent cause of cyanotic congenital heart disease. Its features include subpulmonary stenosis, ventricular septal defect, an overriding aorta, and right ventricular hypertrophy. If the degree of subpulmonary stenosis is severe, right-to-left shunting ensues and cyanosis is produced. In this case, cyanosis occurs across the entire body, not the lower half only.
Transposition of the great arteries (choice E) occurs when the pulmonary artery arises from the left ventricle and the aorta from the right. This is incompatible with life unless a shunt also exists (e.g., ventral septal defect). The degree of whole-body cyanosis depends on the degree of the shunt.
ReKap
Penetrance refers to the proportion of people with a particular genetic change, such as a mutation in a specific gene, who exhibit signs and symptoms of a genetic disorder.
If some people with the mutation do not develop features of the disorder, the condition is said to have incomplete penetrance.
Analysis
The correct answer is C. The situation provided is an example of incomplete penetrance, in which inheritance of a diseased allele does not necessarily result in the disease phenotype. In the image, the disease is shown to be transmitted in an autosomal dominant manner, with the presence of a black dot on the ASO dot-blot analysis corresponding to the presence of the disease. However, individual E possesses the diseased allele but does not exhibit the disease. It is common for diseases with autosomal dominant inheritance to show incomplete penetrance.
Anticipation (choice A) is a phenomenon whereby affected individuals in a family will present with symptoms of a genetic disorder earlier in life with each successive generation. Classic examples of anticipation include trinucleotide repeat diseases such as Huntington disease, myotonic dystrophy, and fragile X syndrome.
Imprinting (choice B) describes a phenomenon whereby certain genes are pre-transcriptionally modified (e.g., methylation, histone acetylation) to affect the transmission of the trait and gene expression in a sex-specific manner. For example, certain gene regions on a chromosome will be pre-transcriptionally modified in a male gamete, which would otherwise be unchanged in the female. Classic diseases involving genomic imprinting include Angelman syndrome and Prader-Willi syndrome.
Pleiotropy (choice D) is a phenomenon whereby a single gene defect affects numerous, seemingly unrelated phenotypes. An example of this is albinism, in which a single gene defect affects pigmentation but can also present with visual problems.
X-linked recessive inheritance (choice E) would be incorrect because hypercholesterolemia is an autosomal dominant disease. Additionally, if this were an X-linked recessive disease it would be highly unlikely that individual F would be affected since she would have to inherit a mutant allele from her mother, who would most likely have a normal genotype.
ReKap
Popliteal artery injury occurs with posterior knee dislocations.
Loss of pulses distal to the injury site requires angiographic evaluation.
Analysis
The correct answer is D. The popliteal artery is the continuation of the femoral artery after the femoral artery passes through the adductor hiatus. The popliteal artery descends posterior to the knee joint and divides into the anterior and posterior tibial arteries (choices A and E) at the lower border of the popliteus muscle.
Because the popliteal artery is the most anterior neurovascular structure in the popliteal fossa and closest to the femur, it is most likely to be injured with a posterior dislocation of the knee.
Diagram showing the arterial circulation of the lower extremities.
The anterior tibial artery (choice A), the posterior tibial artery (choice E), and the fibular artery (choice C: a branch of the posterior tibial artery in the upper leg) are all in the leg distal to the knee and not typically injured in the posterior location of the knee.
The femoral artery (choice B) is in the anterior compartment of the thigh and passes through the adductor (Hunter’s) canal to reach the adductor hiatus. After passing through the hiatus to reach the popliteal fossa, it becomes the popliteal artery.
ReKap
Marfan syndrome is caused by a defect in the fibrillin gene.
Features of this disease include mitral valve prolapse, long limbs and fingers (arachnodactyly), ectopia lentis (dislocation of the lens), and aortic dissection.
Analysis
The correct answer is A. The gross specimen demonstrates the pathognomonic changes of mitral valve prolapse, also known as a floppy mitral valve.
Myxoid, mucopolysaccharide material accumulates within the mitral valve leaflets (myxoid degeneration).
Leaflets acquire a typical hooded appearance as they prolapse into the left atrium during systole. Stretching of the chordae tendineae is usually also noted.
Mitral valve prolapse can be encountered in Marfan syndrome, which this patient had. This is caused by an autosomal dominant mutation of the fibrillin gene. The clinical presentation includes long limbs and fingers (arachnodactyly), ectopia lentis (dislocation of the lens), and a significant risk for developing aortic dissection.
Atrial fibrillation (choice B) can rarely occur secondary to mitral valve regurgitation; this is, however, less likely than the risk of aortic dissection in a patient with Marfan syndrome. Furthermore, atrial fibrillation is typically seen in older adults.
Rupture of the ventricular wall (choice C) is an infrequent complication of myocardial infarction.
Libman-Sacks endocarditis (choice D) occurs with lupus and antiphospholipid syndrome, not Marfan syndrome.
Right ventricular failure (choice E) can be secondary to acutely or chronically increased right ventricular afterload. Patients with mitral valve prolapse and Marfan syndrome are not at significantly increased risk.
ReKap
Venous drainage of the ovaries is from the ovarian veins.
The left ovarian vein enters the left renal vein and then the left renal vein joins with the IVC.
The right ovarian vein drains directly into the IVC.
Analysis
The correct answer is C. The structure indicated by the arrow is the right ovary. Drainage of both ovaries is to the ovarian veins.
The right ovary drains via the right ovarian vein directly into the right vena cava. This is in contrast to the left ovary which drains into the left renal vein, which then flows into the vena cava. This occurs because the ovaries’ embryologic origin is in the retroperitoneum, which is different than the uterus and other pelvic structures. This is why the other pelvic structures utilize the iliac arteries and veins while the ovaries do not.
The left gonadal vein drains into the left renal vein. The right gonadal vein drains into the IVC directly.
The path described in choice A (cervical vein, uterine vein, external iliac vein) is not correct for two reasons. The ovary does not drain to the cervical vein and the uterine vein does not drain to the external iliac vein; it drains to the internal iliac vein.
The path described in choice B (cervical vein, uterine vein, internal iliac vein) is the correct drainage for the uterine cervix, not the ovary.
The path described in choice D (ovarian vein, internal iliac vein) is not correct because the ovarian vein does not drain into the internal iliac vein.
The path described in choice E (ovarian vein, renal vein) would be correct for the left ovary but not the right ovary.
ReKap
Patent ductus arteriosus is a congenital heart defect resulting from the persistence of an embryologic connection between the aorta and the proximal left pulmonary artery.
It produces a machinery-like murmur and can cause cyanosis later in life due to the development of Eisenmenger syndrome.
The left sixth aortic arch in the sixth branchial arch gives rise to the ductus arteriosus.
Analysis
The correct answer is E. This patient has an untreated congenital defect, specifically a patent ductus arteriosus (PDA). The ductus arteriosus connects the proximal left pulmonary artery with the aortic arch. In utero, the umbilical vein provides oxygenated blood to fetal circulation. Since the lungs are not yet functional, blood flow from the pulmonary trunk is shunted to the aorta via the ductus arteriosus. After birth, the initiation of breathing results in decreased pulmonary vascular resistance and an increase in flow through the pulmonary vasculature. Over the next few days, a decrease in serum prostaglandins and increased oxygen tension and bradykinin levels stimulate the closure of the ductus arteriosus, leaving behind a remnant known as the ligamentum arteriosum.
Illustration depicting the route of blood flow in the setting of a patent ductus arteriosus (PDA).
In cases where the ductus arteriosus does not close after birth, blood is shunted from the aorta to the pulmonary artery (a “left-to-right” shunt). During both diastole and systole, pressure in the aorta is higher than the pulmonary artery, thus producing a continuous, “machine-like” murmur. Over time, increased flow through pulmonary vasculature produces pulmonary hypertension, and pulmonary pressures eventually exceed the pressure in the aorta. When this occurs, blood flow will reverse in a process known as Eisenmenger syndrome. Cyanosis occurs because deoxygenated blood from the pulmonary artery enters the systemic circulation, lowering oxygen saturation. Because the ductus arteriosus enters the aorta distal to the brachiocephalic, left common carotid, and left subclavian arteries, patients present with lower extremity cyanosis in PDA-associated Eisenmenger syndrome.
Each of the branchial (pharyngeal) arches is covered by ectoderm on the outside and endoderm on the inside. They are filled with neural crest and mesoderm cells. The neural crest gives rise to cartilage, bones, and ligaments. The mesoderm gives rise to skeletal muscles and blood vessels. The blood vessels that form from the mesoderm in each arch are called aortic arches and are given the same number as the arch in which they form; for example, the artery in the sixth branchial arch is the sixth aortic arch. Each of the aortic arches develops into specific blood vessels in the embryo, as summarized below.
The artery of the sixth branchial arch (sixth aortic arch) gives rise to the proximal pulmonary arteries and the ductus arteriosus.
The artery of the first branchial arch (choice A) mostly degenerates but some of it contributes to the maxillary artery.
The artery of the second branchial arch (choice B) forms the stapedial and hyoid arteries, which typically involute after development.
The artery of the third branchial arch (choice C) forms the common carotid and proximal internal carotid arteries.
On the left, the artery of the fourth branchial arch (choice D) gives rise to the aortic arch. On the right, it forms the proximal subclavian artery.
ReKap
In primary ciliary dyskinesia (PCD), an inherited gene mutation causes structural and functional ciliary defects that result in ciliary arrest or a lack of effective ciliary motion, causing male infertility.
PCD impairs the respiratory clearance of mucus and trapped debris.
Situs inversus, which is associated with dextrocardia, is seen in 50% of patients with PCD.
Analysis
The correct answer is A. This patient’s partner has primary ciliary dyskinesia (PCD), an autosomal recessive disorder that impairs ciliary motility. Principal clinical manifestations include:
Bronchiectasis secondary to an inability to clear mucus and bacteria from the lungs, leading to recurrent pulmonary infections.
Chronic sinusitis from an inability to clear bacterial infections.
Situs inversus (cilia movement helps to determine the position of internal organs during development)
Presents as a complete reversal of the circulatory system and viscera
Dextrocardia (apex of the heart points to the right and auscultation of the heart is best over the right chest) is a reflection of situs inversus
Bronchiectasis + chronic sinusitis + situs inversus = Kartagener syndrome
Chronic otitis leading to hearing loss (recurrent infection of middle ear and Eustachian tube)
Male infertility (sperm immobility)
Decreased female fertility (impaired egg transit through fallopian tubes — may lead to an ectopic pregnancy)
PCD mutations localize to genes encoding ciliary inner and outer dynein arms, assembly proteins, or radial spokes (see figure). Dynein is a molecular motor that causes adjacent microtubule doublets to slide against each other sequentially, resulting in cyclical ciliary bending and beating.
An ostium primum septal defect (choice B), also known as an endocardial cushion defect, causes a hole in the atrial septum near the tricuspid and mitral valves. These defects are the most common cardiac congenital defects in patients with Down syndrome.
A patent foramen ovale (choice C) is a very common defect in which the foramen ovale (connects the two atria) fails to close after birth.
Tetralogy of Fallot (choice D) is a cyanotic congenital cardiac defect characterized by pulmonary stenosis, overriding aorta, ventricular septal defect, and right ventricular hypertrophy. It occurs with increased frequency with chromosome 22 deletions and DiGeorge syndrome. Tetralogy of Fallot would have likely have been diagnosed in childhood, as it usually presents with cyanosis immediately after birth.
Transposition of the great arteries (choice E) refers to a congenital cardiac condition in which the aorta arises from the morphologic right ventricle and the pulmonary trunk arises from the morphologic left ventricle. It is incompatible with life without the presence of a shunt such as a ventricular septal defect. This defect is more common in infants of mothers with diabetes mellitus.
ReKap
Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by defects in the gene that encodes for the low-density lipoprotein (LDL) receptor.
FH is inherited with a gene dosing effect in which homozygotes are more adversely affected than heterozygotes.
Offspring of a homozygote and a genetically normal individual will be affected heterozygotes, with elevated plasma LDL cholesterol levels.
Analysis
The correct answer is E. The nodular lesions described are xanthomas, resulting from accumulations of lipid-laden macrophages. This patient most likely suffers from homozygous familial hypercholesterolemia (FH). FH is an autosomal dominant condition due to mutations in the gene encoding the low-density lipoprotein (LDL) receptor. The effects of this mutation are gene dosage-dependent: homozygous individuals express a more severe phenotype than heterozygous individuals.
FH heterozygotes: LDL cholesterol is elevated to 190-550 mg/dL (normal is <130 mg/dL) and these patients have an increased incidence of atherosclerosis.
FH homozygotes: LDL cholesterol levels exceed 500 mg/dL and affected individuals have numerous xanthomas. These patients often die early in life (typically do not reach mating age) because of myocardial or cerebral infarction.
In this question, both of the patient’s parents are heterozygotes with elevated levels of LDL cholesterol. Considering the patient’s extremely high LDL cholesterol and the presence of xanthomas, he most likely suffers from a homozygous form of the disease causing a congenital absence of LDL receptors. Therefore, when he grows up, even if his partner has no genetic defects in the LDL receptor, their child will definitely have one copy of the mutated gene and will also manifest elevated cholesterol. See the Punnett square below, where “A” is the dominant, affected gene and “a” is the recessive, unaffected gene.
On the horizontal axis is the homozygous dominant male described in this vignette, and on the vertical axis, is the unaffected female mate. 100% of the offspring are affected with the heterozygous form of the disease.
The other choices (choices A, B, C, and D) are incorrect. If you picked choice C, 50%, it may be because you forgot that the male is homozygously expressing the phenotype and not heterozygously expressing the phenotype with this autosomal dominant disease.
ReKap
Chronic systemic hypertension causes:
Increased arteriolar wall thickness at the expense of the lumen.
Decreased arteriolar density.
Decreased total cross-sectional area within the arteriolar lumen.
Analysis
The correct answer is B. Chronic systemic hypertension leads to ↓ arteriolar density, ↑ wall-to-lumen ratio, and ↓ total cross-sectional area.
Arteriolar density
↑ Blood pressure causes reflex arteriolar constriction through local autoregulatory mechanisms. The high pressure causes capillary blood flow to exceed tissue needs, washing out vasodilatory metabolites (e.g., adenosine, K+, and others) and the arterioles constrict.
Chronic vasoconstriction is followed by arteriolar disassembly, which reduces vessel density.
Wall-to-lumen ratio
Hypertension increases vessel wall stress according to the law of Laplace:
Stress = luminal pressure × (lumen radius ÷ 2h), where h = wall thickness.
Arteries and arterioles hypertrophy to increase wall thickness. Lumen internal radius is decreased simultaneously. Both modifications reduce mechanical stress on the vessel walls.
Cross-sectional area
Net arteriolar lumen cross-sectional area is reduced due to ↓ density and ↑ wall-to-lumen ratio.
When the wall-to-lumen ratio decreases, this implies that either the arteriolar wall has thinned or the lumen has increased in diameter. In either case, the total luminal cross-sectional area (directly correlated with lumen diameter) should be inversely related to the wall-to-lumen ratio. This concept eliminated choice A which has both the wall-to-lumen ratio and total luminal cross-sectional area as decreased.
Chronic hypertension leads to arteriolar disassembly, which reduces arteriolar density. Choices C, D, and E are in turn incorrect.
ReKap
Diazoxide opens KATP channels in vascular smooth muscle, causing hyperpolarization and vasodilation.
Opening KATP channels on pancreatic beta cells results in hyperpolarization and decreased calcium entry through voltage-gated calcium channels, leading to decreased insulin secretion in response to glucose.
Analysis
The correct answer is B. Diazoxide, like the experimental agent in the prompt, both vasodilates and decreases insulin release in response to glucose. This drug can be used to rapidly reduce blood pressure during a hypertensive emergency and increase glucose release to reverse hypoglycemia caused by hyperinsulinism. Diazoxide’s mechanism of action is similar to minoxidil, though minoxidil is commonly used to treat hypertension and topically to treat baldness.
The main mechanism behind diazoxide’s effect is potassium channel activation.
Diazoxide-mediated vasodilation:
KATP channel activation relaxes arteriolar smooth muscle cells and causes vasodilation.
Pathway: K+ Efflux → Hyperpolarization → Voltage-gated Ca2+ channel closure → ↓ Intracellular calcium → ↓ Myosin light chain kinase activation → Relaxation.
Diazoxide-mediated hyperglycemia:
KATP channel activation decreases insulin release by pancreatic beta cells, causing hyperglycemia.
Pathway: K+ Efflux → Hyperpolarization → Voltage-gated Ca2+ channel closure → ↓ Exocytosis of stored insulin (see diagram below).
The figure above depicts the process of membrane depolarization that leads to calcium influx.
Atenolol (choice A) is a selective beta-1 adrenergic receptor antagonist and is used as an antihypertensive. These effects are mediated, in part, by blocking beta-1 receptors on the granular cells that secrete renin and by blocking cardiac beta-1 adrenergic receptors. Since vascular smooth muscle does not have beta-1 receptors, there should be no smooth muscle response in the experiment. Also, the pancreatic beta cells do not have beta-1 receptors (they have alpha-2 receptors), so there would be no response there as well. As a side note, remember that overdoses of beta-blockers are generally treated with glucagon.
Hydralazine (choice C) decreases blood pressure through peripheral vasodilation. Unlike diazoxide, hydralazine acts through nitric oxide to increase cGMP and relax smooth muscle tissue. Hydralazine has no effect on either blood glucose or plasma insulin levels. Hydralazine is most commonly used in the treatment of essential hypertension as a single agent or in combination with other medications.
Losartan (choice D), an angiotensin-II receptor antagonist (ARB), would have no direct effect on an isolated vascular smooth muscle cell because it is dependent on the presence of angiotensin II to exert an effect. Pancreatic beta cells do not have angiotensin II receptors.
Phentolamine (choice E), an alpha-adrenergic receptor antagonist, causes vasodilation by inhibiting alpha-1 receptors, which are tonically stimulated by norepinephrine. Experimentally, there would be no direct effect on an isolated vascular smooth muscle cell because there is no norepinephrine present. Additionally, although there are alpha-2 adrenergic receptors on pancreatic beta cells, these receptors may actually inhibit insulin release. Thus, antagonism would increase insulin secretion (although this is not necessarily seen clinically).
ReKap
The mid-thoracic esophagus is located immediately posterior to the left atrium.
The left atrium is comprised of a trabeculated part and a smooth part.
The trabeculated part is derived from the primitive atrium.
The smooth part is derived from the primitive pulmonary vein.
Analysis
The correct answer is B. Placing the ultrasound probe into the mid-thoracic esophagus, facing forward, can produce clear images of the neighboring cardiac structures during transesophageal echocardiography (TEE). The majority of the posterior surface of the heart is occupied by the left atrium, with the esophagus passing immediately posterior to it. Therefore, the closest part of the heart to the ultrasound probe is the left atrium. The left atrium is comprised of a trabeculated part (derived from the primitive atrium) and a smooth part (derived from the primitive pulmonary vein).
Embryonic derivation of various heart structures. The left atrium arises from the primitive atrium and pulmonary vein.
The bulbus cordis (choice A) is positioned ventral to the primitive ventricle after approximately day 24 when the developmental stage of the heart has reached its S-shaped form. Together, the bulbus cordis and the primitive ventricle (choice C) give rise to the ventricles of the heart. At the described position of the ultrasound probe, the closest structure is the left atrium, not the ventricles.
The right common cardinal vein (choice D) and the right anterior cardinal vein together form the embryonic origin of the superior vena cava.
The right horn of sinus venosus (choice E) gives rise to the smooth part of the right atrium, commonly referred to as the sinus venarum.
